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Sem2 > PP > Flashcards

PP Flashcards

1
Q

Differentiate between histology and cytology.
Look at notion

A

H - study of tissues
C - study of cells

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2
Q

Explain why examination of tissue microscopically is important and what information can be obtained from such examination, realising that there is a component of subjectivity.

A

Can observe pathogens and cells.

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3
Q

Describe the processes involved in producing slides for microscopy.

A

Light:
Fix in formalin (stops autolysis as it inactivates enzymes, prevent bacterial growth). Need formalin 10x the size.
Dehydration using alcohol, then replace with xylene
Embed in paraffin wax
Thin section using microtome
Stain (usually H and E - purple and pink)
Mounting - to preserve the tissue and attach coverslip

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4
Q

Briefly outline the principles behind immunohistochemistry and how it aids diagnosis.

A

Antibody linked to enzyme
Antibody will bind to antigenic substance
End product is coloured material that can be seen with light microscope

Cadherins - deficient in some carcinomas
Receptors
Microorganisms
Cytokeratin - intracellular- in all epithelia - can give info about primary site of carcinoma

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5
Q

Recognise the principles behind molecular biology (this will be expanded in session 11).

A
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6
Q

Interpret the common layout of a histopathology report.

A

Clinical details :
Macroscopic : Details of sample size
Microscopic : Description, diagnosis
Conclusion : what the specimen is and what the diagnosis is.

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7
Q

Explain what a frozen section is, giving examples of when they may be indicated.

A

Method of hardening tissue quickly. Not as good as paraffin.

Intra-operative

Aim is to establish presence and nature of a lesion and
influence the course of the operation

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8
Q

How to make a diagnosis

A

Is this inflammatory or neoplastic?
– Is this benign or malignant?
– Is this a primary tumour or a metastasis?

Type of cancer
Grade of cancer
Completeness of excision and if margins are involved, which ones.
Stage of cancer
Likely efficacy of further treatments

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9
Q

Importance of microscopic diagnosis

A

Need microscopic diagnosis before surgery to remove lesion
guides the type and extent of surgery

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10
Q

Describe the common causes of cell injury.

A

Environmental
– Hypoxia
– Toxins/Poisons
– Immune mediated - hypersensitivity or autoimmune
– Physical agents
– Infection
– Nutritional/dietary

Non-environmental
– Genetic
– Ageing

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11
Q

Explain the different mechanisms of cell injury and how they target the
different components of the cell (cell membrane, nucleus etc)

A
  1. Depletion of ATP
    Eg hypoxia - cell deprived of O2 so less OP so no mitochondrial ATP.
    Effects:
    Anaerobic - less glycogen, more lactic acid, lower pH, enzymes damaged.
    Na/K pump - cell swelling and Ca enters
    Ribosomes detach from ER - Reduced protein synthesis so fat deposits
  2. Direct mitochondrial damage
  3. Direct membrane damage - physical agents
  4. Disruption to calcium
    homeostasis
    Effects:
    Ca influx = irreversible
    Activate ATPases, phospholipases, proteases and endonucleases. When lysosomal membranes are damaged their enzymes leak into the cytoplasm.
  5. Oxidative stress (free radicals) - In times of stress all cells reduce their usual
    protein synthesis and increase heat shock protein
    synthesis eg ubiquitin to help repair or degrade.
  6. Direct damage to DNA and
    proteins
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12
Q

Describe and interpret the appearance of injured cells by light and electron microscopy (i.e. cytoplasmic changes)
Look at notion

A

Reversible
• Swelling - pump failure
• Clumped chromatin - lower pH
• Ribosome dispersion - lack of ATP to hold them together
• Cytoplasmic blebs - cell swelling
Intact membrane

Irreversible
Nuclear changes
• Membrane defects
• Lysosome rupture – reflects
membrane damage
• Lysis of endoplasmic
reticulum due to membrane defects

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13
Q

Types of necrosis
Look at notion

A

Coagulative - solid organs, retains ghost outline of cells, protein denaturation
– Liquefactive - loose tissue, no architecture, enzymes break down tissue
– Caseous - TB
– Fat necrosis - fatty areas
– Fibrinoid necrosis

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14
Q

Finish Recognize the most common molecules released by injured cells and how
they may affect the cell/body processed.

A

Potassium
– Enzymes
– Myoglobin

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15
Q

Describe, with examples, the different types of abnormal cellular accumulations that can occur in cells secondary to cell injury.

A

Accumulations can be:
(1) Normal cell components - cerebral oedema - water due to hypoxia cell injury which causes Na to enter so water follows and cell swells.
2) Abnormal components - fat accumulation in hepatocytes in liver cell injury
3) Pigment - eg tattoo pigment phagocytosed and in macrophages of dermis

Reversible • Harmful • Toxic

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16
Q

Explain the different types of pathological calcifications

A
  1. Localised in dying tissue (dystrophic)
    – Most common
    – Nothing to do with calcium metabolism
  2. Generalised (metastatic)
    – Deposition in otherwise normal tissue
    – Metabolic error causing high levels of circulating calcium
    – Can be fatal
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17
Q

Define and explain the clinical terms often associated with cell death (i.e.
types of gangrene, infarction etc).
Look at notion

A

Gangrene = necrosis visible to the naked eye

Infarction = necrosis caused by reduction in arterial blood
flow
– A cause of necrosis – Can result in gangrene

• Ischaemia = inadequate blood supply to tissue
Can result in infarction

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18
Q

Discuss the effects of chronic excessive alcohol misuse and obesity on the
liver (i.e. fatty change, acute alcoholic hepatitis and cirrhosis)

A

Cause of cell injury - Ethanol

Mechanism of cell injury:
1. Increased NADH:NAD
2. Increased fatty acid synthesis 3. Accumulation of fat

Reversible changes: fatty liver disease - Abnormal cellular accumulation

Continues to drink
Mechanism of injury:
– Florid inflammation, this directly damages liver cells (alcoholic hepatitis)
– Continued fat accumulation

• Damaged hepatocytes release enzymes: – ALT/AST (liver function tests)
• Abnormal cellular accumulations: – Bilirubin (jaundice) – toxic!
• Irreversible injury: necrosis, fibrosis and cirrhosis

Hepatic failure

Complications:
Bleeding – Encephalopathy – Ascites

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19
Q

Hypoxia

A

Hypoxia is oxygen deprivation

different causes of hypoxia:
1. Hypoxaemic hypoxia – arterial content of oxygen is low
2. Anaemic hypoxia – decreased ability of haemoglobin to carry oxygen
3. Ischaemic hypoxia - interruption to blood supply
4. Histiotoxic hypoxia – inability to utilise oxygen due to disabled oxidative phosphorylation enzymes

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20
Q

Define 2 types of cell death

A

Apoptosis- Individual programmed cell death
Physiological- embryogenesis, involution of hormone dependent tissue eg thymus
Pathological - viral etc

Necrosis: in a living organism the morphological changes that occur after a cell has been dead some time (seen after 12-24 hours)

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21
Q

Two pathways of apoptosis

A

2 pathways:
Intrinsic - mitochondria release cytochrome C which activate caspases which induce apoptosis.

Extrinsic - death receptors attach to the cell membrane which then activate caspases.

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22
Q

Distinguish diff appearance of apoptosis and necrosis

A

A - Cells shrink • No inflammation
Clumped chromatin. Ribosomes separate from ER.

N - Cells swell
• Characteristic nuclear changes
– Pyknosis (shrinkage) – Karyorrhexis (fragmentation) – Karyolysis (dissolution)

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23
Q

Apoptosis vs necrosis

A

Look at notion

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24
Q

Types of infarction
Look at notion

A

White(no) or red(haemorrhage)
White:
Wedge shaped
Occlusion of end artery
Red:
Haemorrhage into dead tissue • Organs with a dual blood supply • Previous vascular congestion

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25
Q

Types of gangrene
Look at notion

A

Can be dry or wet
Dry is exposure to air and coagulative
Wet is infection and liquefactive
Gas - anaerobic bacteria

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26
Q

Most common injuries

A

Oxidative
Depletion of ATP

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27
Q

What does Complications of infarction depend on

A

– Alternative blood supply
– Speed of ischaemia
– Tissue involved (heart/brain)
– Oxygen content of the blood

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28
Q

Ses2

A
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29
Q

Describe the common causes (aetiology) of acute inflammation

A

• Foreign bodies (splinters, dirt, sutures)
• Immune reactions
• Infections (bacterial, viral, parasitic) and microbial toxins
• Tissue necrosis (any cause)
• Trauma (blunt and penetrating)
• Physical and chemical agents (e.g., thermal injury, e.g., burns or frostbite, irradiation,
environmental chemicals).

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30
Q

Recognise and interpret the clinical signs of acute inflammation and how these relate to tissue changes.
Name the proteins present in inflammation.

A

tumour:
Vasodilatation which increases capillary hydrostatic pressure.
Increased vessel permeability so plasma proteins move into interstitium
This inc interstitial oncotic pressure.
Fluid movement OUT of vessel INTO interstitium so OEDEMA.

rubor, calor, dolor, loss of function

C-Reactive Protein (common blood test – marker of severity)
Fibrinogen
a1 antitrypsin

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31
Q

Explain the tissue changes that occur in acute inflammation

A
  1. Inc arteriole flow and capillary pressure
    Brief vasoconstriction
    Vasodilation of arterioles from chemical mediators such as histamines
    Inc rate of flow
    Capillary pressure rises so fluid moves out
  2. Inc vessel permeability so inc fluid exudate
    Walls of venules become more permeable
    Plasma leaves
    Inc interstitial oncotic pressure
    Inc haematocrit in venules so inc resistance to flow
    Inc pressure
    Inc exudation of fluid into interstitium
  3. Movement of neutrophils from blood into tissue

Inc vessel permeability due to:
Retraction of Endothelial Cells due to Histamine, Nitric Oxide, Leukotrienes
Direct Injury - Burns, toxins, direct trauma
Leucocyte Dependent Injury - Enzymes/toxic oxygen species released by activated inflammatory cells

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32
Q

Evaluate how these tissue changes constitute an effective response to injury

A

When arterioles dilate flow accelerates in the capillaries and capillary pressure rises. These changes 1. increase the delivery of fluid and leucocytes to the area of injury.

Vessel wall becomes more permeable.
2. Interstitial Fluid - Dilutes toxins
3. Exudate - Delivers Proteins eg fibrin – mesh limits spread of toxin and immunoglobulins can carry out adaptive immune response

  1. Fluid drains to lymph nodes so delivery of antigens – stimulates adaptive immune response.
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33
Q

Recognise what a neutrophil is and describe its actions in mediating acute inflammation.
Look at notion for diagram of neutrophils.

A

The primary white blood cell involved in acute inflammation
Trilobed nucleus

Steps
1. Chemotaxis - movement towards chemical attractant from injured cell, bacteria etc.

  1. Activation - switches to a higher metabolic level and becomes stickier.
  2. Margination, Rolling and Adhesion - Stick to walls of venules, then roll while binding to select ns, then trapped when receptors bind to integrins.
  3. Diapedesis - crawl through venules by using collagenase which digests the basement membrane.
  4. Recognition and attachment to bacteria using opsonins eg C3b or antigens.
  5. Phagocytosis - engulf and digest bacteria. Phagosomes fuse with lysosomes, Produce secondary phagolysosomes.
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34
Q

Recognise and explain the action of some of the key chemical mediators involved in acute inflammation

A

Chemical Messengers
Control and co-ordinate the inflammatory response

Vasoactive amines - histamine in vasodilation and inc vascular permeability.

Vasoactive peptides - bradykinin in vasodilation and inc vascular permeability.

Mediators from phospholipids - prostaglandin in vasodilation and fever. Inhibited by NSAIDs as they inhibit cyclooxygenase.

Complement components- C3a in inc permeability.

Cytokines and chemokines - involved in Chemotaxis. TNF involved in cachexia.

Endotoxins

Vasodilation- Histamine + Serotonin (from platelets) Prostaglandins
Permeability- Histamine, Bradykinin
Chemotaxis - C5a, Bacterial products
Pain - Bradykinin, Prostaglandins

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35
Q

Understand the local and systemic short and long term consequences of acute inflammation and interpret how these might affect organs.
4 each

A

Local complications:
Damage to normal tissue due to by-products of phagocytosis.
Obstruction of tubes and compression of organs due to exudate eg fallopian tubes
Loss of fluid from surface wounds
Pain causes muscle atrophy, psycho-social consequences and loss of function.

Systemic complications:
Fever - pyrogens eg Prostaglandins which act on hypothalamus to alter temperature to kill bacteria.
Treat with NSAIDs.
Leucocytosis - neutrophilia
Acute phase response - Inducing rest by malaise, reduced appetite, altered sleep, tachycardia.
Septic shock - Huge release of chemical mediators. Widespread vasodilatation = hypotension = tachycardia so eventually multi-organ failure.

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36
Q

Describe the features seen in some common clinical examples of acute inflammation: COVID-19 infection,, s, ascending cholangitis

A

Acute appendicitis - Blocked lumen due to Faecolith.
Accumulation of bacteria + exudate
Increased pressure -> perforation

Pneumonia

Bacterial meningitis
Inflammation of meninges
Many causative organisms:
Group B Streptococcus, E.Coli, Neisseria meningitides
Signs and symptoms: Headache, Neck stiffness, Photophobia, Altered mental state

Abscess - Accumulation of dead and dying neutrophils with associated liquefactive necrosis.
Can cause compression of surrounding structures so pain and blockage of ducts.

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37
Q

Understand a few clinical examples of inherited disorders of the acute inflammatory process: Hereditary angio-oedema, Alpha-1 antitrypsin deficiency, Chronic granulomatous disease.

A
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38
Q

What is Inflammation and phases?

A

The response of living tissue to injury.
It is immediate, short, innate,stereotyped, limits damage.
4 phases:
Vascular- Changes in blood flow Accumulation of exudate

Cellular Phase
Delivery of neutrophils

Controlled
Chemical mediators

Protective
But can cause local and systemic complications

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39
Q

Wh at happens after acute inflammation?

A

1 - Complete resolution
Mediators have short half lives so Diluted/inactivated/degraded.
Vessel calibre and permeability returns to normal.
Neutrophils undergo apoptosis and get phagocytosed.
Exudate drained via lymphatics If tissue architecture is preserved, can undergo regeneration.

2 – Repair with connective tissue (fibrosis) - If there has been substantial tissue destruction.

3 – Progression to chronic inflammation - Prolonged inflammation with repair

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40
Q

Ses 3

A
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41
Q

Understand how pathologists interpret images

A

Biopsy and resection
H and E
Immunohistochemistry, immunofluorescence,
electron microscopy
Low or high power

Benign - infection or inflammation
Malignant- type of cancer
Cancer - stage/grade, has it all been removed?, features that indicate chemo/radio?

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42
Q

Explain what structures are stained by haematoxylin and eosin

A

H = purple - nuclei
Eosin = pink - cytoplasm and extracellular matrix

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43
Q

Differentiate between histology and cytology - notion for pics, understand resection

A

Histology - solid tissue i.e. biopsy or resection
Tissue structure - Look for specific things:
– tumour invasion
– tumour grade
– special tests
• Invasive • Expensive • Timely
• More accurate

Cytology - individual cells + fluid aspirate
Eg smear test
Individual cells
• Benign vs Malignant - only one question
• Less invasive • Cheap • Quick
• Less accurate

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44
Q

Recognise the histological appearance of WBCs, macrophages, epithelium - notion

A
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45
Q

Recognise the histological appearances of benign and malignant neoplasms, carcinomas, granulomatous inflammation, apoptosis and necrosis- notion, what is pleomorphism

A
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46
Q

Describe the common causes (aetiology) of chronic inflammation

A
  1. When it takes over from acute inflammation
  2. When it begins without any proceeding acute inflammation, e.g. in some chronic infections
    such as tuberculosis, in some autoimmune conditions such as rheumatoid arthritis, with prolonged exposure to some toxic agents
  3. When it develops alongside and superimposed on acute inflammation, e.g., in on-going
    bacterial infection, persistent irritation
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47
Q

Explain the action of the cells principally involved in chronic inflammation -5 general types and 9 subtypes notion for cell pics

A

Macrophages - phagocytosis, antigen presentation, synthesise and release of many mediators, presenting antigens, stimulating angiogenesis, inducing fibrosis, inducing fever

Lymphocytes- T and B cells.
Helper T cells release cytokines to influence other inflammatory cells
Cytotoxic T cells destroy pathogens
B cells differentiate into plasma cells to produce antibodies to neutralise pathogens

Eosinophils - release mediators in hypersensitivity reactions and attack large parasites

Fibro/myofibroblasts - fibro produce connective tissue substances such as collagen, elastin and glucosaminoglycan. Differentiate into myo which contract.

Giant cells - fusion of macrophages.
Langerhans - nuclei in periphery - TB
Foreign body - random, small body then phagocytoses or else sticks
Touton - horseshoe - high lipid content leisons along with foam cells.

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48
Q

describe complications of chronic inflammation and how do they affect organs notion
4 types

A

Fibrosis - fibroblasts are stimulated by cytokines to produce excess collagen .
Initially helps wall off infected area and makes scar tissue but then replaces normal tissue which impairs function.
Eg chronic cholecystitis, liver cirrhosis

Involvement in Inappropriate immune response - when antibodies attack wrong targets, mediators are released that cause inflammation so it is a disease process eg RA.

Atrophy - due to reduced function

Impaired Function
Eg inflammatory bowel disease Rarely = increased function (eg thyrotoxicosis in Graves’ Disease)

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49
Q

Describe the features seen in chronic inflammation conditions:
Rheumatoid arthritis, Chronic cholecystitis, Liver Cirrhosis. Notion

A

RA - immune system attacks body tissue and mediators are released that cause inflammation.

Chronic cholecystitis - chronic cholecystitis - Repeated bouts of acute inflammation -> chronic inflammation, Fibrosis of gall bladder wall (thickened and pale).

Cirrhosis - End stage damage to liver.
Fibrosis and attempted regeneration.
Alcohol, Hepatitis, Drugs & toxins, Fatty liver disease.

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50
Q

Describe Ulcerative colitis, Crohn’s disease notion

A

Ulcerative colitis - affects large bowel only.
Continuous inflammation. Affects superficial wall (muscles and submucosa) only.
No granulomata.
More likely to have rectal bleeding than Crohns.

Crohn’s disease- all of GI, discontinuous patches of inflammation, affects full bowel wall, sometimes granulomata, less likely to have rectal bleeding than UC.

Both idiopathic
Abdominal pain
Altered bowel motion
Weight loss

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51
Q

Definition of granuloma and granulomatous inflammation. Function of granuloma.

A

Granuloma - collection of macrophages that look like epithelial cells (epithelial histiocytes) with surrounding lymphocytes.

A granuloma is the body’s way of dealing with particles that are poorly soluble or difficult to eliminate for some reason.

Granulomatous inflammation is a type of chronic inflammation in which granulomas are seen.

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52
Q

2 types of granuloma

A

Foreign body - Destruction and removal of foreign material
Few lymphocytes
Eg large splinter

Immune mediated - Destruction and removal of pathogens (bacteria/fungi) - insoluble but antigenic particles that cause cell-mediated immunity
Can be idiopathic
Can undergo central necrosis
Many lymphocytes
Can be harmful as they occupy parenchymal space within an organ

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53
Q

Describe the aetiology of granulomatous inflammation (e.g. foreign body material, infections, sarcoidosis, Crohn’s disease) and recognise and explain the microscopic appearances notion

A

Foreign body reaction

Infections by mycobacterium eg tuberculosis and leprae as they are difficult to destroy due to thick cell wall and mycolic acids.

Crohn’s Disease - Non-necrotising granulomata in GI tract

Sarcoidosis - Non-necrotising granulomata in skin, lymph nodes, lungs - organs throughout body - idiopathic

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54
Q

Ses 4 Regeneration and Repair

A
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55
Q

Describe the differences between labile, stable and permanent tissues and be able to give examples of each.
If labile continuously replicating - tumour?

A

Labile - Continuous replication of cells. Continuous cell cycle. Eg epithelium, haematopoietic tissue

Stable - Normally low level of replication but can undergo rapid replication if required. Left cell cycle but can re-enter.
Eg Liver, kidneys, pancreas, bone, endothelium, smooth muscle

Permanent - Cells do not replicate. Left cell cycle. Eg neurons, skeletal muscle, cardiac muscle

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56
Q

Discuss the role of stem cells and know what is meant by unipotent, multipotent and totipotent.

A

Stem cells differentiate and self-renew. Replace dead/damaged cells.
Totipotent- all cell types - embryonic stem cells
Multi - several - haematopoietic
Uni - one - epithelial

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57
Q

Describe (at a basic level) how cells communicate and their involvement with cell signalling

A

Cell to cell contact - contact inhibition
Isolated cells replicate until they
encounter other cells. Cadherins bind between cells and inhibit further proliferation. Defective in cancer.

Local mediators - growth factors
Polypeptides that act on cell surface. Causes cell to enter cell cycle and proliferate. Eg VEGF, epidermal GF, platelet derived GF, tumour necrosis factor.

Hormones

With local mediators and hormones communication can be:
Autocrine
Paracrine
Endocrine - synthesised by endocrine organ and transported in blood to target.

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58
Q

Explain and discuss the processes involved with regeneration, resolution and fibrous repair/organisation and how these affect different tissues. How does comp resolution after acute inflammation happen?

A

Regeneration - if collagen framework intact labile or stable can regenerate using stem cells.

Fibrous repair - happens if collagen framework destroyed, chronic inflammation or necrosis of permanent tissue.

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59
Q

Fibrous repair 4 steps

A
  1. Bleeding & Haemostasis
  2. Inflammation
    Phagocytosis of necrotic tissue debris
  3. Proliferation of:
    Capillaries (angiogenesis), Fibroblasts, Myofibroblasts (synthesise collagen), Extracellular Matrix - all make granulation tissue. This contracts and closes the defect.
  4. Remodeling
    Maturation of scar: Reduced cell population, Increased collagen, Myofibroblasts contract to shrink scar
60
Q

Fibroblast pic notion and myofibroblast

A
61
Q

Collagen synthesis and types

A

Type 1 - Bones, tendons, ligaments etc
4 - Basement membranes

In myo/fibroblast cytoplasm
Pre-pro collagen undergoes Vitamin C dependent hydroxylation to become pro-collagen which has cross-linked alpha chains that form triple helix.
Leaves cell. C and N terminals of procollagen cleaved to form tropocollagen.
Tropocollagen crosslinked and many of them together form collagen fibres.

62
Q

Describe and recognise the histological components of granulation tissue notion

A
63
Q

defects of collagen synthesis

A

Scurvy - Inadequate hydroxylation of pre-pro collagen. Defective triple helix = defective collagen. Bleeding gums, tooth loss, bruising of skin, fatigue

Inherited:
Ehlers-Danlos syndrome – a heterogeneous group of six inherited disorders where the
collagen fibres lack tensile strength.
Skin is hyperextensible and susceptible to injury
Joints are hypermobile - joint dislocations.
Wound healing is poor. Because the collagen in internal organs is also affected
patients can suffer from rupture of the colon, large arteries, corneal rupture and retinal detachment.

Osteogenesis imperfecta - COL1A or 2A gene mutation. They have blue sclerae as there is too little collagen in the sclerae making them translucent. also have hearing loss, dental abnormalities, hypermobility.

Alport syndrome – usually an X-linked disease. Type IV collagen is abnormal and this results
in dysfunction of the glomerular basement membrane, the cochlea of the ear and the lens of the eye. Patients, usually male, present with haematuria. This progresses to chronic renal failure. They also have neural deafness and eye disorders.

64
Q

Explain and distinguish between primary and secondary intention.

A

Primary - occurs in incised, closed, non-infected wound with apposed edges (sutured).
Minimal clot and granulation tissue.
Epidermis regenerates, dermis undergoes fibrous repair - disruption of epithelial basement membrane but death of only some epithelial and connective tissue cells.

Secondary - Significant tissue loss, excisional, infected
Unapposed edges (Infection/ulcer/abscess)
Abundant clot, inflammation and granulation tissue
Considerable wound contraction required (Myofibroblasts)
Dermis requires significant repair
Epidermis regenerates from edges

65
Q

Discuss the healing processes of bone fractures.

A

1.Haematoma which fills the gap and surrounds the bone injury. It provides a foundation for the subsequent cell growth.

  1. A fibrin mesh and then granulation tissue is formed. Platelets and inflammatory cells release cytokines. These activate osteoprogenitor cells to osteoclastic and osteoblastic activity.
  2. Soft callus (also called procallus or fibrocartilaginous callus) forms at about one week. It consists of fibrous tissue and cartilage within which woven bone begins to form. Forms a bulge around the fracture site.
  3. Hard callus appears after several weeks. It is laid down by osteoblasts. The
    bone formed initially is woven bone.
  4. Formation of lamellar bone which is stronger than woven bone.
  5. Remodelling of the bone occurs in response to mechanical stresses placed on it. Bone not physically stressed is resorbed and the outline of the bone is re-established.
66
Q

Describe the local and systemic factors influencing the efficacy of healing and repair
Is primary intention same as regeneration?

A

Local:
Size, location, type - intention, regeneration or scarring
Blood supply
Local infection + Foreign bodies - persistent inflammation

Systemic:
Age
Anaemia, hypoxia, hypovolaemia - poorer o2 delivery
Obesity - inc wound tension
Diabetes - microangiopathy
Drugs - steroids inhibit collagen synth, antibiotics clear up inflammation and infection
Vitamin C deficiency inhibits collagen synth
Malnutrition - no protein synth

67
Q

Describe the complications of fibrous repair

A

Insufficient Fibrosis
Wound dehiscence

Excessive Fibrosis
Keloid Scar

Adhesions
Fibrous bands - cause obstruction of tubes

Loss of function - Replacement of specialised tissue by fibrous tissue

Disruption of architecture

Excessive scar contraction - Constriction of tubes and flexed flexion deformities(contractures)

68
Q

Appreciate and explain some of the special aspects of regeneration and repair in: cardiac muscle, liver, peripheral nerves, cartilage, central nervous system.

A
69
Q

Ses 5

A
70
Q

Define haemostasis + clotting. 3 steps of haemostasis.

A

Haemostasis is the stopping of haemorrhage from injured vessel.
Clotting is the process whereby blood becomes a solid mass when it makes contact with connective tissue.

Haemostasis:
The severed artery contracts to decrease the pressure downstream
Platelet plug
Blood clot from fibrin

71
Q

What does vessel wall do to cause clotting

A

Vessel wall is made up of 3 layers tunica intima (endothelium), tunica media (smooth muscle) and tunica adventitia (connective tissue).
Does:
Vasoconstricton
Production of vWF - essential for platelet adherence
Exposure of collagen and tissue factor initiates activation of clotting factors. They are present in Tunica Adventitia of the vessel wall.
Endothelium secretes tissue plasminogen activator and thrombomodulin that oppose clotting

72
Q

2nd step of haemostasis - platelet plug,

A

Platelets have no no nucleus - From cytoplasm of megakaryocytes - Life span = 7-10 days

When vessel is injured:
• ADHESION - Platelets adhere to collagen via vWF

• ACTIVATION/SECRETION - Activated by collagen surfaces, ADP, thrombin, thromboxane A2.

• AGGREGATION - Cross linking of platelets to form a platelet plug

73
Q

the coagulation system

A

Intrinsic(involves factors in blood) and extrinsic pathway( tissue factor - thromboplastin outside blood)
Join by factor 10
Each step is conversion of a proenzyme (zymogen) to an active enzyme
Amplification system to generate thrombin (IIa)
Thrombin(enzyme) converts soluble fibrinogen into insoluble fibrin • Enmeshes initial platelet plug to make stable clot

Fibrinolysis - releases D-dimers

74
Q

Describe and begin to interpret the common tests in a coagulation screen.

A

3 basic tests • Performed on platelet poor plasma
(centrifuged)

Activated partial thromboplastin time (APTT) - intrinsic - factors 8,9,11,12 - if prolonged one of them is deficient - VIII (haemophilia A) and IX (haemophilia B)

Prothrombin time (PT) - extrinsic factor 7

Thrombin time (TT) - fibrinogen to fibrin

Deficiencies in Factors V, X, thrombin and fibrinogen prolong both the APTT and PT as they are in the common pathway

75
Q

Factors that oppose clot formation

A

Dilution by blood flow

fibrin degradation products - D dimers

Protein C + Protein S: Thrombin binds to an endothelial cell receptor called thrombomodulin
• The resulting complex activates protein C
• This then inactivates Factors VIIIa and Va
• Protein S is a cofactor for activated protein C

Antithrombin - Plasma protein that inactivates thrombin and several other clotting factors
Activated by heparin on the surface of endothelial cells
Prevents the spread of a clot, by rapidly inactivating clotting factors, that are carried away from the immediate site of the clot by the flowing blood.

76
Q

discuss bleeding disorders and thrombotic disorders e.g. thrombocytopenia, DIC, TTP

A

Thrombocytopenia symptoms- purpura, petechiae, mucosal bleeding, epistaxis, menorrhagia.
causes:
Dec production - marrow aplasia, sepsis

Inc consumption- immune and non-immune
Immune - Thrombocytopenic purpura (antibodies against enzyme which prevents multimers of VWF. Platelets stick to these multimers. Causes MAHA.)

Non-immune - Hypersplenism ( Enlargement of the spleen– Reduction in the number of circulating blood cells).
haemolytic uraemic syndrome (Low RBCs and platelets, Bloody diarrhoea, fever, vomiting, kidney failure).
DIC (Pathological activation of coagulation. Numerous microthrombi are formed which leads to consumption of clotting factors and platelets so MAHA. Always has trigger eg malignancy, sepsis, pre-eclampsia).

Thrombotic disorder - Thrombophilia
Congenital - deficiency in natural anticoagulants (protein C, protein S and antithrombin)
Abnormal factor 5 - factor v Leiden - resistant to activated protein C.
Acquired = antiphospholipid syndrome (due to antiphospholipid antibodies)

77
Q

discuss the pathophysiology, treatment and complications of coagulation disorders eg DIC, Haemophilia A & B, and von-Willebrand disease.

A

Acquired - DIC
Thrombus forms in vessels leading to ischaemia, necrosis and organ damage.
Inc bleeding due to consumption of platelets and clotting factors.
Clotting tests affected – usually raised PT/INR, raised APTT, low fibrinogen and raised D dimers

Congenital:
H A - X-linked recessive • Congenital lack of factor VIII, Prolonged APTT and normal PT • Treated with recombinant factor VIII
B - Congenital reduction in factor IX, Treated with infusions of recombinant FIX, otherwise similar
– Recurrent haemarthroses – Joint pain and deformity – Prolonged bleeding post dental extraction

VWD - autosomal dominant, VWF deficient - binds to factor 8 and helps activity. Also responsible for platelet adhesion to vessel wall.
Causes inc bleeding time and APTT (intrinsic pathway).
Symptoms:
Spontaneous bleeding from mucous membranes (nosebleeds) • Excessive bleeding from wounds eg dental • Menorrhagia
Unlike H spontaneous joint or muscle bleeds are rare.
Vessel wall abnormalities

78
Q

Describe the mode of action of commonly used anticoagulants, how they might be monitored and the complications of anticoagulants.

A

Anti-platelet
Aspirin - blocks formation of thromboxane A2
in platelets
Clopidogrel/ticagrelor – block platelet ADP

Complications- bleeding
Warfarin - Warfarin – stop, give Vitamin K - affects clotting factors that require Vit K which are factors 2(thrombin),7,9,10 (factor 7 dec due to lack of Vit K first as it has shortest half life).

Heparin – stop, give protamine sulphate which binds to heparin and stops it from working. Heparin activates antithrombin lll which dec activity of F10 and thrombin.

79
Q

Thrombosis

A

Formation of a solid mass of blood within the circulatory system.
Clot = mass of blood outside the vessel wall

80
Q

How is a thrombus formed?
Virchow’s triad?

A
  1. Vessel Wall Damage
  2. Blood flow - turbulent
  3. Blood components - hypercoagubility
81
Q

damage

A

Wall
Atheroma
Inflammation
Direct injury
Damage to heart

Blood flow
Stasis - Narrowing, immobility, LBP
Turbulent blood flow – Defects in wall and heart valves,

Components
Hypercoaguable- smokers, pregnancy, trauma

82
Q

Arterial and venous thrombi notion

A
83
Q

Fibrinolysis

A

tPA = tissue plasminogen activator
Plasminogen to plasmin
Plasmin degrades fibrin and dissolves thrombus
Fibrin degradation products eg. D dimers (detected in blood tests)

84
Q

Outcomes of thrombosis

A

Lysis - break down when small, Fibrinolytic system active, Blood flow re-established

Propagation - Progressive spread of thrombosis
Distally in arteries
Proximally in veins

Organisation - Ingrowth of fibroblasts and capillaries, lumen obstructed

Recanalisation - One or more channels form through area of organising thrombus, incomplete blood flow

Embolism - Part of thrombus breaks off
 Travels through bloodstream
 Lodges at distant site

85
Q

Effects of venous thrombosis on the tissue and locations

A

congestion  oedema  ischaemia  infarction

Cavernous sinus thrombosis
Subclavian vein thrombosis
Budd Chiari and IVC thrombosis
Uteroplacental thrombosis
Deep vein thrombosis, DVT

86
Q

arterial thrombosis on the tissue
And locations

A

ischaemia  infarction  depends on site and collateral circulation
Cerebral A. Carotid A.
Coronary A. Mesenteric A Renal A.
Femoral/
Iliac /
Popliteal A.

87
Q

Embolism

A

Embolism is the blockage of a blood vessel by solid, liquid or gas at a site distant from its origin.
>90% of emboli are thrombo-emboli
Other types:
Air - medical equipment
Amniotic fluid - tear in amniotic membrane - pregnancy - causes haemorrhage
Nitrogen - scuba
Tumour cells
Fat + bone marrow- bone fractures

88
Q

Thromboembolism locations and what it causes

A

Veins - causes pulmonary embolism in pulmonary artery
Massive PE = death
Small = is in peripheral artery, infarct
Multiple = hypertension

Heart - thromboembolism due to endocardial thrombus (causes MI), vegetations, atrial fibrillation.
Fragments into aorta and then affects systemic arteries such as renal (renal infarcts), mesenteric (bowel ischaemia).

From carotid arteries development of atherosclerotic plaque with thromboemboli causes ischaemic stroke.
From Abdominal aorta - Atherosclerotic plaque or aneurysm with development of thromboembolism causes acute limb ischaemia.
From iliac/femoral causes limb ischaemia.

89
Q

Treatment of thrombus & thromboemboli
Notion for chart

A

Mobilise+leg compression
Thrombolysis - streptokinase
CT PA for pulmonary embolism
Heparin
DOACs are anti factor 10, eg rivaroxaban - better than warfarin(easily bleed by overdosing, need lots of blood tests)
Mechanical
Embolectomy

90
Q

Ses 6

A
91
Q

Define arteriosclerosis, atherosclerosis and atheroma

A

Atherosclerosis – a disease of large and medium sized arteries that begins in the intima.
Plaques are formed in the arterial wall and these are filled with atheroma.
The plaques often calcify.

Arteriolosclerosis = hardening of the arterioles.
This disease affects arterioles throughout the body but especially those of the kidney.
It has little or no connection with atherosclerosis and
usually occurs secondary to severe hypertension or in diabetes mellitus.

Atheroma is the necrotic core of the atherosclerotic plaque. It consists of dead cells, debris and cholesterol crystals.

92
Q

Explain the cellular events that lead to the formation of atherosclerotic lesions notion

A
  1. Chronic endothelial insult
  2. Lipid droplets from LDLs, and monocytes cross and accumulate in the intima.
    The lipids become oxidised and the macrophages ingest the lipid - foam cells
  3. Smooth muscle cells migrate into the lesion from the media and start to proliferate - fatty streak.
  4. Some smooth muscle cells
    lie over the plaque forming a ‘roof’.
    This roof is reinforced by
    collagen, elastin etc - fibrous cap.
    As the endothelium
    stretches gaps appear between the endothelial cells. Platelets adhere to the
    gaps.
  5. Cells in the centre of the plaque die and necrosis develops.
    The dead cells release cholesterol and cholesterol crystals appear in the plaque.
    Small blood vessels grow into the plaque from the adventitia and the plaque may undergo calcification.
93
Q

Components of an atherosclerotic plaque.

A

Cells:
endothelial cells - Altered permeability to lipoproteins

platelets - migration of smooth muscle cells (PDGF)

neutrophils - Secrete proteases - inflammation

macrophages - foam cells + smooth muscle cells migration

smooth muscle cells - foam cells, synthesise collagen

Lymphocytes - migration of smooth muscle cells

Lipid:
intracellular (foam cells) and extracellular (pools)

Extracellular matrix:
collagen, elastin, proteoglycans

94
Q

and proposed theories

A
95
Q

Describe the variable macroscopic appearances of atherosclerosis e.g. fatty streak, simple plaque and complicated plaque
Notion

A

Fatty streak
Lipid deposition, slightly raised yellow area in the intima

simple plaque / fibroatheroma
Raised yellow/white, irregular outline, widely distributed, enlarge and coalsece

Complicated plaque
Yellow and red (haem and thrombosis), irregular, rough, hard and calcified

96
Q

Microscopic appearances

A

Fatty streak - Proliferation of smooth muscle cells Accumulation of foam cells Extracellular lipid

Simple plaque - Fibrosis (fibrous cap), Necrosis, Cholesterol clefts

complicated plaque - Disruption of the internal elastic lamina, Damage extends into the media, New vessels grow into plaque (from adventia), Plaque fissuring

97
Q

Plaque Complications

A
  1. Ulceration – the fibrous cap is eroded from underneath and the core of the plaque is exposed to the blood - highly thrombogenic.
  2. Thrombosis on the plaque – often on ulcerated - occlude lumen.
  3. Spasm at the site of the plaque – caused by vasoconstrictors released from thrombi.
  4. Embolisation – of pieces of exposed atheroma or overlying thrombus.
  5. Calcification – in and around the plaque making the artery even stiffer.
  6. Haemorrhage – of one of the new vessels within the plaque. expands the
    plaque = vessel occlusion or break the plaque open.
  7. Aneurysm formation – a local dilatation may result when elastic tissue within the arterial wall is destroyed - weakens the wall - rupture.
  8. Rupture of the atherosclerotic artery – with resulting bleeding. This occurs as a result of a
    weakened media.
98
Q

Recognise the common sites of atherosclerosis and the sequelae/complications of atheroma at these sites,

A

• Heart - myocardial infarction, chronic ischaemic heart disease, arrhythmias, cardiac failure and sudden cardiac death
• Brain – transient ischaemic attacks (TIAs), cerebral infarction, multi-infarct dementia,
• Kidneys – hypertension, renal failure,
• Legs – peripheral vascular disease, gangrene, Acute limb ischaemia
• Bowel - ischaemic colitis, malabsorption, acute bowel ischaemia.
Abdominal Aorta - Aneurysmal formation, rupture

These conditions are either due to narrowing/blockage of vessels or embolism of plaque material or thrombus that has formed on a plaque.

99
Q

Risk factors

A

Age

Gender - women protected by oestrogen until menopause

Hyperlipidaemia - high plasma cholesterol + high LDL
Cause:
Apolipoprotein defects - ApoA1, ApoE
Lipoprotein lipase
LDL receptor mutations
Signs - corneal arcus, tendon xanthomas, xanthelasma
Treat:
Dec cholesterol + LDL in diet
Statins
Low fat + high fibre
Aspirin

Cigarette smoking

Hypertension

Diabetes mellitus - IHD, cerebro and peripheral vascular disease

Alcohol

Infection - Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus

100
Q

How to reduce atherosclerotic burden

A

• Statins (lipid lowering)
• Anti-hypertensives
• Exercise
• Normal BMI
• Non smoker
• (Alcohol) – in moderation!
• Balanced diet to reduce diabetes risk - Mediterranean
• Diabetic medication • CANTOS – targeting inflammation in atherosclerosis –
Canakinumab (monoclonal Ab targeting IL-1Beta)

101
Q

Ses 7

A
102
Q

Understand and describe the principles of the cell cycle.
Notion

A

Size of population:
• cell proliferation
• cell differentiation
• cell death by apoptosis

G0 - permanent exit
G1 - cellular contents duplicated
S-chromosomes duplicated
G2 - checks for error, inc in cell size and proteins

Restriction point - End of G1- nutrients, GF, DNA damage
G2 checkpoint- cell size and replication
Metaphase checkpoint - spindle attachment

Cyclin dependent kinases - phosphorylase proteins to allow passage through restriction points.

103
Q

define: Hyperplasia, hypertrophy, atrophy,
metaplasia, aplasia, hypoplasia, involution and dysplasia

A
  1. Hyperplasia – cells increase in number - only in labile or stable eg bone marrow or liver. Reversible.
  2. Hypertrophy – cells increase in size
  3. Atrophy – cells become smaller
  4. Metaplasia – cells are replaced by cells of a different type. Not across germ layers. Not in striated muscle or neurones. Still fully differentiated.

Aplasia –The complete failure of a specific tissue or organ to develop

Hypoplasia –The congenital underdevelopment, or incomplete development, of a
tissue or organ

Involution –The normal programmed shrinkage of an organ

Dysplasia – The abnormal maturation of cells within a tissue

104
Q

Explain notion

A

Hyperplasia:
Physiological- hormonal or compensatory (tissue damage) - inc bone marrow production in hypoxia, After birth hyperplasia for lactation.
Pathological - psoriasis - epidermis thicker

Hypertrophy:
more cellular components.
Physio - heart in athletes, Smooth muscle hypertrophy in uterus in pregnancy, Skeletal muscle.
Path - anoxia in heart, in BPH obstructed urinary flow so trusser muscle works harder so bladder hypertrophy.
When one kidney removed compensatory hypertrophy.

Atrophy:
Cellular - shrinkage of cell but survival. Red function + components
Organ - loss of parenchyma and replaced by connective tissue. Remove cause.
Physio - dec in size of uterus after birth, thymus gland from 20yrs
Path - disuse eg after fracture. denervation. senile due to inadequate blood supply in permanent tissue eg brain in artherosclerotic cerebrovascular disease. Pressure. Immunological - pernicious anaemia causes gastric mucosa to lose glands that produce intrinsic factor?

Metaplasia:
columnar epithelium (fragile) undergoes metaplasia to become
squamous epithelium (more resilient) but mucus secretion lost.
common on surface linings.
Physio - Myeloid metaplasia of the spleen
- splenic tissue to bone marrow tissue when it is destroyed by disease. Stratified squamous more resistant in Salivary gland ducts and pancreatic ducts, Renal pelvis and renal stones.
In smoking replace by squamous which cannot produce mucus - squamous cell carcinoma
Barrera oesophagus- Acid reflux causes replaced by secretory glands - oesophageal adenocarcinoma.
Fibroblasts in skeletal muscle to osteoblasts - Traumatic myositis ossificans.

105
Q

Explain

A

Thymus aplasia - immune conditions in infants
Aplastic anaemia - bone marrow cells fail to proliferate - embryonic

Hypoplasia - embryonic - congenital - not opp - renal hypoplasia, testicular hypoplasia, chambers of heart

Atreasia - oesophageal and duodenal

Reconstitution- several cells involved. Small blood vessels in healing.

Involution - thymus, pronephros

Dysplasia -cervical cancer

106
Q

Hallmarks of cancer and enabling characteristic

A
  1. Resistance to apoptosis
  2. Angiogenesis
  3. Resistance to growth stop signals
  4. Self sufficiency in growth signals
  5. Cell immortalisation due to telomeres- no limit on proliferation
  6. Metastasise

Enabling- genetic instability - alterations in chromosomal segregation that causes accelerated accumulation of mutations that are present in malignant neoplasms.

107
Q

S

A
108
Q

S

A
109
Q

S

A
110
Q

Ses 8

A
111
Q

Understand, explain and define the terms: neoplasm,, tumour, cancer, metastasis notion

A

Tumour = Any clinically detectable lump or swelling

Neoplasm = means ‘new growth’. an abnormal growth of cells that persists after the initial stimulus is removed.
Malignant when it invades surrounding tissue and can spread.

Metastasis = Malignant neoplasm that has spread from its original site to a new non-contiguous site.

Cancer = a malignant neoplasm

112
Q

Dysplasia, anaplasia, pleomorphism, progression, differentiation and in situ. Finish

A

dysplasia - pre-neoplastic alteration in which the cells show
disordered tissue organisation Reversible
Can exhibit considerable pleomorphism

pleomorphism - increasing variation in size and shape of cells and nuclei.

Differentiation = the process of becoming different by growth or development.

Progression - neoplasm emerges from single founding cell. characterised by the accumulation of yet more mutations.

113
Q

Describe differences between benign and malignant tumours including macroscopic and microscopic features and biological behaviour. Notion.

A

Behaviour- Malignant can spread

Macro - Benign grow in a local area and so have a pushing outer margin. Malignant have an irregular outer margin and may show areas of necrosis and ulceration.

Micro - Benign closely resembles the parent tissue - well differentiated - low grade.
With worsening differentiation individual cells have increasing nuclear size and nuclear to cytoplasmic ratio, increased nuclear staining (hyperchromasia), more mitotic figures and pleomorphism.

114
Q

Describe and understand the difference between in-situ and invasive malignancy.

A

In-situ = no invasion through epithelial basement membrane. Invasive means it’s penetrated.

115
Q

development of neoplasms and explain the concept of clonality.

A

Neoplasia is caused by accumulated mutations in somatic cells.
The mutations are caused by initiators, which are mutagenic agents, and promoters, which cause cell proliferation.
In combination result in an expanded, monoclonal (single founding cell) population of mutant cells.

Can be inherited instead of external mutagenic agent (chemicals eg smoking + alcohol, radiation, infection eg HPV).

116
Q

Explain how proto-oncogenes and tumour suppressor genes are involved as well as 2 other types

A

Genes targeted by cancer causing mutations:
Growth promoting proto-oncogenes

Growth inhibiting tumour suppressor genes

Genes that regulate apoptosis - abnormalities so less cell death

Genes involved in DNA repair -
Impair the ability of the cell to repair non-lethal genetic damage so cells acquire mutations at accelerated rate - mutator phenotype.

proto-oncogenes become abnormally activated (oncogenes then to oncoproteins) = neoplasm formation. Drive proliferation. Sometimes they impart a completely new function on the affected gene (Gain-of-function” mutations). Need 1 damaged allele.

Tumour suppressor genes, which normally stop cell proliferation become inactivated.
Need 2 damaged alleles.

117
Q

Understand the reasoning behind the nomenclature given to benign and malignant neoplasms and the exceptions to this rule e.g. adenoma, papilloma, carcinoma, benign mesenchymal tumours
such as leiomyoma and lipoma, sarcomas, gliomas etc. notion

A

benign or malignant, the type of tissue the tumour forms and sometimes the gross morphology (e.g. cyst or papilloma).

Benign neoplasms end in –oma. Malignant ones end in –carcinoma if epithelial or -sarcoma if stromal. Some neoplasms are called “-blastomas”, - children - immature precursor cells.

118
Q

Identify the types of cancers that most commonly arise in certain organs and why finish

A
  • Bladder – transitional cell carcinoma
  • Oesophagus – squamous cell carcinoma, adenocarcinoma
  • Stomach/Bowel – adenocarcinoma
  • Skin – squamous cell carcinoma, malignant melanoma,
    basal cell carcinoma - Lung – adenocarcinoma, squamous cell carcinoma, small
    cell carcinoma - Breast/Prostate – adenocarcinoma - Brain –astrocytoma - Thyroid/Pancreas/Uterus – adenocarcinoma - Cervix – squamous cell carcinoma
119
Q

Describe and understand the processes of invasion and metastasis

A

Invasion
Breach of the basement membrane with progressive infiltration and destruction of the surrounding tissues
Metastasis
Spread of tumour to sites that are physically discontinuous from the primary tumour

1) GROW AND INVADE AT THE PRIMARY SITE with breach of the basement membrane.
(2) ENTER A TRANSPORT SYSTEM AND LODGE AT A SECONDARY SITE;
(3) GROW AT THE SECONDARY SITE TO FORM A NEW TUMOUR (COLONISATION)

CELLS MUST EVADE DESTRUCTION BY IMMUNE CELLS.

120
Q

Describe the cellular alterations that are required for invasion to occur notion
Niche?

A

• Altered adhesion
Reduction in E-cadherin expression (so sticks to other cells less) +Changes in Integrin expression(basement membrane)

• Stromal proteolysis
Altered expression of proteases, notably matrix
metalloproteinases (MMPs). Degrade basement membrane to allow for invasion.

• Motility
Propels itself forward into stroma. Involves changes in the actin cytoskeleton.

cell takes on a phenotype more
akin to a mesenchymal cell/stromal cell so known as
epithelial to mesenchymal transition.

Niche

121
Q

Understand the processes that determine the site of a metastasis

A

Regional drainage:
of blood, lymph or coelomic fluid (fluid in body cavities).
Lymphatic metastasis = lymph nodes as it drains there - Breast cancer goes to the ipsilateral axillary lymph nodes.
transcoelemic spread -
other areas in the coelemic space or adjacent
organs
blood-borne metastasis - next capillary bed.

Seed and soil phenomenon:
INTERACTIONS BETWEEN MALIGNANT CELLS AND THE LOCAL TUMOUR ENVIRONMENT (I.E. THE NICHE) AT THE SECONDARY SITE.

122
Q

Identify the neoplasms that most frequently spread to the bones and the difference between lytic and sclerotic lesions.

A

Metastases are most common malignant bone tumours - axial - haematogenous spread

osteolytic lesions due to destruction of the bone tissue

osteosclerotic metastases as it causes increased production of disorganised abnormal bone - prostate cancer

123
Q

Describe the local and systemic effects of neoplasms
anaemia, DIC and pro-thrombotic effects etc.

A

Local:
1. Direct invasion and destruction of normal tissue
2. Ulceration at a surface leading to bleeding
3. Compression of adjacent structures
4. Blocking tubes and orifices
5. Raised pressure due to tumour growth or swelling
(brain)

Systemic:
Inc tumour burden + cytokines secretion = dec appetite and weight loss (cachexia), malaise, Immunosuppression(could be due to direct destruction of bone marrow), thrombosis.

Production of hormones(usually benign).

Paraneoplastic Syndrome - not readily explained symptoms eg Hypercalcaemia (myeloma), Syndrome of Inappropriate ADH Secretion causes hyponatraemia (small cell lung cancer).

Miscellaneous - neuropathies, pruritus, fever, clubbing, myosotis, hypoglycaemia.

124
Q

Ses 9

A
125
Q

intrinsic and extrinsic factors of development of neoplasias

A

Intrinsic:
heredity (inherited mutation - BRACA 1 gene causes breast cancer), older age (more exposure to extrinsic factors and immune system gets worse) and gender (hormonal - oestrogen)

extrinsic:
environment - chemicals, radiation and infection
behaviour - high BMI, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use

126
Q

List extrinsic carcinogenic agents and understand their mechanisms of action, including occupational hazards e.g. chemicals –
radiation -
infections - Epstein Barr virus,

A

Chemicals - initiators:
aromatic amines eg 2-napthylamine - dye industry and smoke - bladder cancer,
natural products e.g aflatoxin in fertilisers - liver cancer, asbestos - buildings - mesothelioma.
Pro-carcinogens converted to carcinogen by cytochrome P450 enzymes in liver.
Need promoters for proliferation.

Radiation
UV light - doesn’t penetrate further than skin - skin cancer
Ionising - radon - damage DNA ( single and double strand breaks) or generate free radicals.

Infections:
Affect genes that control cell growth eg HPV - cause cervical carcinoma- express E6 that inhibits p53 so cell cannot undergo apoptosis.
Or cause chronic tissue injury - regeneration acts as promotor for mutations or new mutations from DNA replication errors eg Hep B and C cause chronic liver cell injury, H pylori causes chronic gastric inflammation, parasitic flukes cause inflammation in bile ducts and bladder mucosa.
HIV lowers immunity so allows carcinogenic infections to occur.

127
Q

Cancer rules

A

1) there is a long delay between carcinogen exposure and malignant neoplasm onset
(2) the risk of cancer depends on total carcinogen dosage
(3) there is sometimes organ specificity for particular carcinogens

6 hallmarks:
1) can produce their own Growth signals
2) resistance to growth stop signals
3) no limit on division
4) angiogenesis
5) resistance to apoptosis
6) can invade tissue

128
Q

Understand and describe the functions of proto-oncogenes, and caretaker genes in neoplasia, e.g.
oncogenes – ras, c-myc and c-erbB-2 (Her-2); tumour suppressor genes- and p53.

A

Tumour Suppressor Genes
both alleles must be damaged for transformation
Abnormalities in these genes leads to failure of growth inhibition
Example - Retinoblastoma gene - key negative regulator of G1/S cell cycle checkpoint.

Proto-Oncogenes
Oncogenes are created by mutations in proto-oncogenes and encode proteins
called oncoproteins that have the ability to promote cell growth in the absence of
normal growth promoting signals.
Example - RAS

DNA repair genes
Caretaker genes prevent accumulation of DNA damage.
Chromosome aggregation during mitosis can be abnormal in malignant cells due to accelerated mutation rate - genetic instability- caretaker gene are TS genes that maintain stability.

129
Q

Understand and describe the stages of carcinogenesis and the alterations in growth control required to achieve this e.g. initiation, promotion and progression.

A

First, somatic cells are exposed to environmental carcinogens (chemicals, radiation, infections) that are initiators and cause mutation.

Promoters cause sustained proliferation so there is a monoclonal population of mutant cells.

During progression the cells acquire further activated oncogenes or inactivated tumour suppressor genes - cells with all the hallmarks.of cancer.

130
Q

Identify medical conditions that are associated with an increased risk of malignancy e.g ulcerative colitis and cirrhosis.

A

Cirrhosis is associated with hepatocellular carcinoma, and ulcerative colitis is associated with colorectal cancer due to prolonged injury and inflammation to the organs.

131
Q

Identify tumours that can be inherited and describe the understanding behind this e.g. and colorectal cancer,

A

In inherited cancers germline mutations cause
malignant neoplasms indirectly by affecting DNA repair.

Hereditary Non-Polyposis Colon Cancer (HNPCC) Syndrome - autosomal dominant - Germline mutation affects one of several DNA mismatch repair genes eg MSH2,MSH6.

Familial breast carcinoma - BRCA1/BRCA2 genes - repairing double strand DNA breaks

Familial adenomatous polyposis (FAP) - Fault in the APC gene

Retinoblastoma- RB gene - autosomal dominant

132
Q

two hit hypothesis.

A

Neoplasias can be sporadic or familial.

For familial cancers, the first hit was delivered through the germline and affected all cells in the body. The second hit was a somatic mutation.

For sporadic both hits must be somatic and occur in the same cell.

133
Q

Ses 10

A
134
Q

List commonest types of cancer in adults and children and the leading causes of cancer-related death

A

Adult - Lung, female breast (15-54), prostrate (men-45+), bowel carcinomas
Children - leukaemia and lymphoma

Most cancer deaths = lung cancer

135
Q

Define tumour stage
Describe TNM, convert TNM to stages, Duke’s and Ann Arbor

A

Tumour stage is a measure of the overall burden of the malignant neoplasm.

T = size of primary tumour
N = extent of regional lymph node involvement
M = metastatic spread via the blood

• Stage 1 = early local disease
• Stage 2 = Advanced local disease (N0, M0)
• Stage 3 = regional metastasis (N1, M0)
• Stage 4 = advanced disease with distant metastasis (M1)

Ann arbor - breast carcinomas
Stage 1,2,3 tubule formation (3 means very poorly differentiated)
Stage 1,2,3 nuclear pleomorphism
Stage 1,2,3 abnormal mitoses

Dukes - colorectal cancer
Duke A - small - going through through muscle wall
B - eroding completely through muscle wall
C - lymph node involvement
D - liver metastases (or any other metastases)

136
Q

Describe what is meant by tumour grade and understand its significance

A

Grade describes the degree of differentiation of a neoplasm.

G1 = well-differentiated
G2 = moderately differentiated
G3 = poorly differentiated
G4 = undifferentiated or anaplastic

137
Q

Describe the principles behind the different treatments for cancer - surgery and radiotherapy

A

Surgery
Neoadjuvant- Treatment is given prior to surgical excision to reduce the size of the primary tumour
Adjuvant- Treatment is given after surgical removal of a primary tumour to eliminate subclinical disease

Radiotherapy
Kills rapidly dividing cells in G2 of the cell cycle by triggering apoptosis by causing DNA damage which is detected by cell cycle checkpoints.
External beam - aimed at tumour.
Internal - systemic (radioactive iodine) or local (brachytherapy- capsules near tumour).
There are lifetime dose limits. Fractionated doses to limit damage to normal tissue.

138
Q

Describe the principles behind the different treatments for cancer notion

A

Chemotherapy
Kills cancer cells that have spread. Used in combination.
Cisplatin - cross link DNA strands, antibiotics eg Doxorubicin inhibits DNA synthesis by inhibiting DNA topoisomerase, antimetabolites eg flurouracil mimic DNA substrates and plant-based disrupt mitotic spindle formation.

Hormone Therapy
Selective oestrogen receptor modulators (SERMs)
– Tamoxifen – Bind to oestrogen receptors so block oestrogen.

Treatments targeted to specific molecular alterations eg target oncogenes - Imatinib which inhibits fusion protein in CML.

Immunotherapy - immune checkpoint inhibitors, T-cell transfer therapy, monoclonal antibodies, treatment vaccines (oncolytic virus therapy - cancer cells cannot kill herpes simplex)

139
Q

Describe the use of tumour markers in diagnosis and monitoring of disease
Notion

A

Various substances are released by cancer cells into the circulation (and in urine and faeces)

Measured for diagnosis, monitoring tumour burden, assess response to therapy and recurrence.

Hormone - Human Chorionic Gonadotrophin (hCG), calcitonin - testicular tumours, medullary thyroid carcinoma
Specific proteins - Prostate specific antigen (PSA)– prostate carcinoma
Fetoproteins - alpha-fetoprotein - hepatocellular carcinoma
Mucins and glycoproteins - CA-125 - ovarian carcinoma

140
Q

Cancer Screening
Benefits and risks

A

Meant for healthy people with no symptoms at all.

Benefits:
Attempts to detect cancers as early as possible when the chance of cure highest
More effective treatment
Reduce complications and death
Can help people make better health decisions eg stop smoking.

Risks:
Lead time bias
Length time bias
Selection bias
Not always accurate - over diagnosis
Anxiety
Could still go on to develop condition even with neg test

141
Q

Screening programme requirements

A

Must be sig public health problem
Treatment and cure with early detection
Safe, inexpensive
Result in better health outcomes

Measures of performance
• Incidence
• Reduction in mortality
• Interval cancers

Sensitivity- ability to identify positive people as positive
Specificity- identify neg as neg

142
Q

W hat screening programmes are available in the UK?

A

Cervical - HPV - 25-64
Breast - 47-73yrs
Bowel - 60-74 yrs

143
Q

Ses11

A
144
Q

Understand and describe the key molecular tests that are currently being performed on certain cancers
(a) Lung cancers

A

Adenocarcinomas:
Oncogenes - both build up drug resistance
EGFR - more Asian - mutations cause activation of TH signalling pathway- cell diff and proliferation - gefitinib which is anti TK inhibitor - better than platinum based chemo drugs - PCR - deletion
ALK - fusion of gene - IHC or PCR - young not smokers - ATP kinase inhibitors eg crizotinib
KRAS - PCR - smokers - on going clinical trials

Small and non small cell:
Tumour suppressor genes
p53 mutations

Small cell:
Tumour suppressor
RB1 mutations

145
Q

(b) Melanoma

A

BRAF mutation - V600E mutation - Activation of MAPK pathway

• Anti BRAF drugs = dabrafenib and trametinib medication
Tumour resistance can develop on BRAF inhibitors alone, so combine with MEK inhibitor (trametinib)

If lacking BRAF mutation- IHC
Block PDL1 ligand on tumour cells so T cells can detect and kill cancer cells - increase in cytokine
production and cytolysis. - Nivolumab and Pembrolizumab - drug resistance and side effects.

146
Q

how similar information can be of use in other major cancers (e.g. colorectal, gynaecological).

A

IHC

Cancer cells produce Growth factors to stay alive and proliferate - PDGF (stromal cell proliferation) and TGF beta (angiogenesis, produces ECM, suppress immune response)
Block TK receptors on growth factors to prevent proliferation

Block PDL1 ligand

Metastatic urothelial carcinoma – PDL1 Head and neck cancers mets – PDL1 Colorectal cancer – DNA mismatch repair enzymes

147
Q

Generally how do cancer cells stay alive

A

Mutate proto-oncogenes to oncogenes so result in cell proliferation
• Mutate Ts genes (double hit) e.g. p53, Rb, APC, WT1, BRCA1 &2 gene, MSH and MLH
• Overexpress anti-apoptotic factors e.g. Bcl2 (Normally bcl2 inhibits apoptosis)
• Inhibit pro-apoptotic signals (e.g. p53, caspases)
• Overexpress growth factors and/or growth factor receptors.
• Mutate DNA repair mechanisms (MLH and MSH)

Sem2 (23 decks)

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